Mitochondrial complex I activity in microglia sustains neuroinflammation.
Luca Peruzzotti-JamettiC M WillisG KrzakR HamelL PirvanRosana-Bristena IonescuJ A ReiszHiran A PragM E Garcia-SeguraV WuY XiangB BarlasAlva M CaseyA M R van den BoschAlexandra M NicaiseL RothG R BatesH HuangP PrasadA E VincentChristian FrezzaCarlos Pardo-HernándezGabriel BalmusZoltán TakátsJohn C MarioniAngelo D'AlessandroMichael P MurphyIrina I MohorianuStefano PluchinoPublished in: Nature (2024)
Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3 .
Keyphrases
- oxidative stress
- induced apoptosis
- low grade
- inflammatory response
- multiple sclerosis
- neuropathic pain
- cell cycle arrest
- reactive oxygen species
- cerebrospinal fluid
- high grade
- bone marrow
- cerebral ischemia
- acute myeloid leukemia
- endoplasmic reticulum stress
- lps induced
- lipopolysaccharide induced
- spinal cord
- immune response
- risk assessment
- signaling pathway
- single molecule